The incidence of pancreatic cancer has increased during the past decades throughout the world, and ranks as the fourth and sixth leading causes of cancer in North America and the European Union respectively (1). This high rank is due to a very poor overall survival (OS) rate (less than 4%), which is illustrated by an annual incidence rate of pancreatic cancer almost identical to the mortality rate. In Canada for example, 3800 new cases were expected to be diagnosed in 2008 with 3700 anticipated deaths from this cancer.
Diagnosis is difficult because there are no noticeable symptoms in early stages, and signs are common with many other illnesses. Furthermore, pancreas location behind other organs renders its imaging more difficult. Diagnosis is usually performed when cancer has already disseminated to other organs. In combination with this late detection, pancreatic cancer displays a poor response to chemotherapy, radiation therapy, and surgery as conventionally used. For patients with advanced pancreatic cancer, the OS rate is less than 1% at five years, whereas for the rare patients diagnosed at an early stage, when surgery is possible, the after resection OS rate climbs to 20% (2). These numbers emphasize the need for an early detection and a new treatment concept of pancreatic cancer.
Current detection methods mostly rely on imaging and are summarized in Table 1.
TABLE 1Current pancreatic cancer detection methods (adapted from cancer.gov)ImagingComputed Tomography (CT) ScanUltrasonographyTransabdominal UltrasoundEndoscopic UltrasoundMagnetic Resonance Imaging (MRI)Endoscopic Retrograde CholangiopancreatographyPercutaneous Transhepatic CholangiographyBiopsiesFine-Needle Aspiration (FNA) BiopsyBrush BiopsyLaparoscopyLab testsBilirubin and other substances
The most sensitive and specific screening tool currently available seems to be the endoscopic ultrasound (3, 4), but its invasive features restrict its use to the screening of high risk populations, namely kindred with minimum two affected first-degree relatives or with known hereditary pancreatic cancer. Another inconvenience of endoscopic ultrasound is that its use is recommended to be associated to other methods such as computed tomography and endoscopic retrograde cholangiopancreatography (5). Diagnosis is confirmed exclusively on analysis of a biopsy. Thus, in addition to being invasive, this multi-step detection and diagnosis process only establishes the presence of an already developed tumor and does not identify risks of developing cancer.
New technologies such as genomics, proteomics, metabolomics and glycomics, have been used in the search for blood-based tumor markers, and have identified glycoproteins, more specifically highly glycosylated mucins, as main tumor markers in all kinds of cancer (6). Among these highly glycosylated mucins, which can be detected by specific monoclonal antibodies, the Cancer Antigen 19-9 (CA 19-9) is present primarily in pancreatic and biliary tract cancers, but also in patients with other malignancies (e.g. colorectal cancer) and benign conditions such as cirrhosis and pancreatitis. CA 19-9 is detected in most proteomics studies in pancreatic cancer serum samples (such as (7)), but its low specificity does not recommend it as a pancreatic cancer biomarker. Anecdotally so far, another glycosylation-related potential biomarker of pancreatic cancer is the core fusylation of biantennary glycans of RNase I, which displayed a 40% increase in the serum of two pancreatic cancer patients relative to two healthy controls (8).
Another well-known serum marker of pancreatic cancer is CEA (carcinoembryonic antigen), with an average reported sensitivity and specificity of both 65% (7). HIP/PAP-I and MIC-1 (macrophage inhibitory cytokine I) are also classical serum markers (9, 10). According to one study, MIC-1 and CA19-9 seem the markers with the highest sensitivity and specificity, in the sense of specificity vs. chronic pancreatitis (and not vs. colon cancer for example), when compared to osteopontin, TIMP-1 and HIP/PAP-I (9).
The use of CA19-9 as a marker is now recommended in combination with other markers, such as the mutation status of pancreatic cancer-related oncogenes like K-ras (2). K-ras is reported to be mutated in 78% of pancreatic adenocarcinomas (11). Molecular events in pancreatic carcinogenesis have been extensively studied (12), and beside K-ras, p53, p21, p16, p27, SMAD4, and cyclin D1 are a few of these genes whose mutations or alterations in expression have been associated to pancreatic cancer (12). However, evidence regarding their application as prognostic indicators is conflicting. For instance, there is no consensus on the association between mutation in p53 and decreased survival (12).
MicroRNA profiling has also been performed for pancreatic cancer, with the identification of some common microRNAs specifically altered (13-15).
Protein markers show the advantage of simple screening through an ELISA (Enzyme-linked immunosorbent assay) method, and research in this field is therefore very intensive. Newer proteomics studies have identified additional protein markers, such as apolipoproteins A-I and A-II, and transthyretin (7), all decreased in serum of pancreatic cancer patients, as well as MMP-9, DJ-1 and A1BG, each of which is overexpressed in pancreatic juice from cancer patients (16).
The involvement of apolipoproteins is interesting since they participate in lipid metabolism (17) and other members of this family have been associated to cancer (18).
The fatty acid composition of lipids in plasma and bile from patients with pancreatic cancer has also been analyzed (19, 20), even though neither of these studies has detailed the chemical subfamilies of the altered lipids. Plasma from pancreatic patients showed significantly lower levels of phospholipids that contain the side chain 18:2(ω6), 20:5(ω3) or 22:5(ω3), without distinction of lipid classes (19). Bile from hepatopancreaticobiliary cancer patients was found to contain a much lower level of phosphatidylcholines without distinction of side chains (20).
Since diabetes mellitus (DM) has a high prevalence in pancreatic cancer patients and is frequently of new onset, research has also been aimed at determining whether DM can be utilized as an early pancreatic cancer marker (21). A 2-fold increase of the glucagon/insulin ratio was found in the blood of pancreatic cancer patients relative to healthy controls, and at a cut-off of 7.4 ng/mU glucagon/insulin, pancreatic cancer induced new-onset DM could be discriminated from type 2 DM with 77% sensitivity and 69% specificity (21).
Overall, the methods described above are not ideally suited for large-scale population screening (either for low compliance or low sensitivity and specificity except in the case of a still-to-optimize multiple method combination), and most are capable of detecting pancreatic cancer after the formation of a tumor only. As a result, there still remains a need for accurate methods of detection, particularly for methods to detect early stages of the disease.